Acylated aromatic compound is chiefly used in pharmaceutical industries. Analgesics (painkillers) are a very well known group of drugs that include asprerine, acetaminophen [Tylenol] and ibuprofen [Motrin, Advil and Medipren]. In addition of their analgesic properties, ibuprofen and asprerine are members of non-steroidal anti-inflammatory group of drugs and are thus used to reduce swelling and inflammation. Ibuprofen was introduced as a carboxylic acid in 1969, to help provide relief of rheumatoid arthritis. It is believed to be gentler on stomach than aspirin. It metabolites rapidly by the body, usually leaving the body via urination within 24 hours of intake. Ibuprofen is a main component for Advil®, Bayer®, Midol 200®, Motrin IB® and Nuprin®. It is used for the treatment of inflammation and pain caused by rheumatoid arthritis and osteoarrthritis, as well as soft tissue injuries, such as tendentious and bursitis. It is also used for the rapid relief of fever and in mild to moderate pain, such as menstrual cramps.
The industrial process for manufacturing of ibuprofen starts with the acylation of isobutylbenzene in the presence of conventional Friedel-Crafts catalysts, described as under.
(A) Boots Process
Boots company of England in 1960 developed a process, which is covered in U.S. Pat. No. 3,385,886, having six steps for the production of ibuprofen. It starts with the acylation of isobutylbenzene in the presence of AlCl3 by using acetic anhydride as an acylating agent. This multi step process results in large quantity of unwanted waste chemical as by products. Much of the waste that is generated as a results of many atoms of the reactant not being incorporated into the desired products (Ibuprofen) but into by-products. Consequently, process has poor atom economy/atom utilisation. (B) Hoescht Process.
It is a three-step synthesis of ibuprofen, which is taught in U.S. Pat. Nos. 4,981,995 and 5,068,448. The Hoescht process also starts with the acylation of isobutylbenzene in the presence of HF by using acetic anhydride as an acylation agent. Compared to Boots process, hoescht process is more eco-friendly, but still the utilisation of hazardous HF for acylation is not safe from handling point of view.
Chemical equation: 
Research efforts to find eco-friendly and safer catalysts, which can replace AlCl3 and HF, have been directed in the literature and are reviewed here.
Reference is made to the work of E. Nandanan., et al., Indian J. of Chemistry, Vol-37B, December 1998, pp-1221-1227, wherein the preparation of 4-acyl isobutylbenzene using AlCl3 and acetyl chloride as an acylating agent is taught. Nandanan et al. used dichloromethane as a solvent. This process has disadvantages of the separation of the catalyst and non-regenerability of the catalyst as well as long reaction time, which is not industrially feasible.
Reference is made to the work of P Andy, et al., J. of Catalysis-192, 215-223 (2000), wherein the Beta zeolite based acylation of isobutylbenzene using acetic anhydride as an acylating agent is taught. This process has disadvantage of low conversion (12% after 20 hours) and it is not economical to commercialize.
Reference is made to the work of Bich Chichi, et al., J. of Mol. Cat.-42 (1987)-229-235, wherein the Friedel-Craft acylation of aromatic compound (BTX) with carboxylic acid over cation exchanged montmorillonite is taught. This process has disadvantage of poor selectivity towards the para position during the acylation of toluene.
Reference is made to the work of C. De Castro, et al., J. of Mol. Cat.-A:Chemical-134 (1998) 215-222, wherein the acylation of xylene is reported using crotonic acid as an acylating agent in the presence of heteropoly acid and large pore zeolite. This process has disadvantages like, in some case, significant amount of alkylation also occurs leading to generation of undesired by-products and loss of starting compound.
Reference is made to the work of AJ. A. van der Weerdt in his personnel communication wherein the acylation of toluene by isobutyryl chloride in the presence of AlCl3. This process has disadvantages like more than stochiometric amounts of aluminum chloride is used due to complexation with the ketone, need to have a post reaction effluent treatment process and use of corrosive and irritant AlCl3. The major drawback of the above stated process is separation of catalysts after completion of the reaction. This necessitates a long, expensive treatment following hydrolysis, extraction of the organic phase, separation of organic and aqueous phase and even drying of latter. Further, there are problems with aqueous saline effluent which has to be neutralised and which necessities additional operation. The Lewis acid cannot be recycled, as it has been hydrolysed.
Reference is made to the work of I. Akhrem, et al., J. Chem Soc. Comm. P. 257, Vol-3, February 1993, wherein the acylation of benzene is reported by acetyl bromide employing Al2Br6 as catalyst to p-tertiary butylacetophenone. This process having disadvantages of waste generation and non-recoverable catalysts as well as requirement of catalysts/reagents which is more than stochiometric amount.
Reference is made to the work of Y. Izumi, et al., Chem. Lett.-P. 1987, 1992 Vol-B 10, wherein the acylation of p-xylene by using benzoyl chloride/anhydride is done in the presence of heteropoly acid. This process has disadvantage like, occurrence of simultaneous alkylation in the presence of heteropoly acid, which leads to generation of undesired by-product.
Reference is made to the work of Lapierre R. B, et al., U.S. Pat. No. 4,899,008, February 1990, wherein the alkylation of benzene and toluene with C2 to C4 alkanes over acidic zeolites is reported. Benzene was reacted with C3H8 over H-ZSM-5 at 385-399° C./6184 kPa for 49 hours to give MePh, 9.92%. This process having disadvantage of operation at very high temperature and pressure.
Reference is made to the work of Klein, Alfons, Fiege et al., Ger. Off. D. E. 3839853, 31 May 1990, wherein the alkylation of p-Cresol with cyclohexanol or cyclohexene is done in the presence of acidic zeolite. This process has the disadvantages of operation at high temperature and pressure and low conversions.
Reference is made to the work of Davydov, D. V, et al., Izv. Akad. Nauk, SSSR, Ser Khim, 1990 (3), 708-710 (RUSS), wherein LnCl3 (Ln=Pr, Dy, Er, Sm, Yb) and Yb(O3SCF3) are used as a catalyst for the electrophilic acylation of benzene and toluene with acylchloride and benzaldehyde. This process has disadvantages of multi-step reaction and non-regeneration of the catalyst.
Reference is made to the work of Nakatani, Jinro, kamoto et al., Jp: 09, 278705 wherein benzene is acylated with CH3CH2COOH in the presence of zeolite-beta at 270° C. to give about 10% of propiophenone. This process has disadvantages of high temperature and very long reaction time which discourages commercial utilization of the process.
Reference is made to the work of Choudary, et al., (India).Jpn. Kokai Tokkyo Koho Jp 2001278833 A2 10 Oct. 2001, 16 pp, wherein the acylation of isobutylbenzene is done using acetic anhydride as an acylating agent in the presence of nanocrystalline zeolite. This process has the disadvantages of utilizing nanosized materials, which makes the whole process more costly. Wt. % conversion of isobutylbenzene was only 30 wt. %.
Reference is made to the work of Eun Joo Jang, Kyung et al., J. of Molecular Catalysis A, 138(1999)-25-36, wherein they have reported regioselective synthesis of ibuprofen via palladium complexes. In this process, ibuprofen is synthesised by hydrocarbonylation of 1-(4-isobutylyphenyl) ethanol with carbon monoxide and water. This process has disadvantage of the utilisation of carbon monoxide gas, which is hazardous, and very difficult to handle; furthermore, in this process, 4-isobutylacetophenoe is produced by conventional Friedel-Craft acylation of isobutylbenzene.
Reference is made to the work of Botella, P, et al., J. Catal., 195(1),161-168 (English)2000, Wherein the acylation of toluene was carried out with acetic anhydride over beta zeolite in a stainless-steel autoclave at 150° C. by keeping arene/anhydride ratio of 10 to 20. This process is having disadvantages of high temperature and also the need of a large amount of acetic anhydride, which will needed to be separated from the product and unused toluene.
Reference is also made to the Assignee's earlier U.S. Pat. No. 6,384,285 titled “Process for the preparation of 4′-isobutylacetophenone” which is incorporated herein as reference. The aforesaid U.S. Patent teaches a process for the preparation of 4'-isobutylacetophenone from isobutylbenzene which comprises reacting isobutylbenzene with acetic anhydride as an acylating agent in the presence of a zeolite beta catalyst at a temperature ranges between 60 to 165 degree. C. for 2-12 h separating the catalyst by filtration from the reaction mixture and recovering the product by a conventional method. The Inventors would like to mention here that the aforesaid U.S. Patent does not teach use of a solvent during the process of acylation of isobutylbenzene using aceticanhydride. The Inventors have surprisingly found that use of some specific solvents during the process of acylation increases the percentage conversion and also the selectivity towards para position. The Applicants have also found that not all solvents are able to increase the percentage conversion and the selectivity. For example, when solvents such as cyclohexane, dichloroethane, dichloromethane and nitromethane are added during the process of acylation, the conversion does not take place. In view of the above, it is submitted that the nature of the solvent added during the process of acylation is very critical. The success of a particular solvent in increasing the percentage conversion and the selectivity cannot be determined merely by extrapolation and it needs lot of research and intellectual input. Hence, the present invention should not be considered as being obvious over the U.S. Pat. No. 6,384,285.